Valtropin

SIDE EFFECTS

Pediatric Patients With GHD

In a clinical study in which Valtropin (somatropin injection) ® 0.053mg/kg/day (vs. the same dose of an active somatropin control) was administered to 98 children with GHD for 12 months, the following adverse events were seen most frequently (≥5.0% in either treatment group): headache, pyrexia, cough, respiratory tract infection, diarrhea, vomiting and pharyngitis (see Table 7). The incidence of all of these adverse events were similar in the 2 treatment groups, and these adverse events reflect very common pediatric illnesses.

During this study, a very modest degree of glucose intolerance was observed
in the 98 patients treated with Valtropin (somatropin injection) ® for 12 months (which was comparable
to that observed in the comparator group). No de novo cases of overt diabetes
mellitus were diagnosed. See PRECAUTIONS, General regarding somatropin-induced
glucose intolerance.

Out of 98 patients with pediatric GHD randomized to treatment with Valtropin (somatropin injection) ®
in the pivotal study described above, 26 (26.5%) had preexisting central hypothyroidism.
Exacerbation of this preexisting central hypothyroidism appeared to be common.
During 12 months of Valtropin (somatropin injection) ® treatment, 18 out of these 26 patients (~69%)
with preexisting central hypothyroidism (who were being treated with a thyroxine
preparation prior to study entry) required up-titration of their thyroxine replacement
dose (primarily based on declining levels of free T4). On the other hand, none
of the 72 patients without preexisting central hypothyroidism manifested de
novo central hypothyroidism while on-study. See PRECAUTIONS,
DRUG INTERACTIONS.

In addition, during the clinical trial described above, low titer anti-rhGH antibodies* were reported in 3 patients treated with Valtropin (somatropin injection) ® (vs. 1 patient treated with the comparator), and low titer anti-host cell protein antibodies were observed in 2 patients treated with Valtropin (somatropin injection) ®. These antibodies appeared after 6 months of treatment, disappeared after 12 months of treatment, and did not attenuate the growth response of these children.

*As with all protein pharmaceuticals, a small percentage of patients may develop
antibodies to the protein. Anti-growth hormone antibodies with binding capacity
lower than 2 mg/L have not been associated growth attenuation. In some patients,
when binding capacity was greater than 2 mg/L, interference with growth response
was observed in published data. Any patient with well documented pediatric GHD
who fails to respond to Valtropin (somatropin injection) ® therapy should be tested for neutralizing
antibodies to rhGH and undergo a careful evaluation to rule out other causes
of growth failure (see DOSAGE AND ADMINISTRATION).

In published literature, leukemia has been reported in a small number of pediatric GHD patients treated with somatropin. It is uncertain whether this increased risk is related to the pathology of GHD itself, somatropin therapy, or other associated treatments such as radiation therapy for intracranial tumors. So far, epidemiological data have failed to confirm the hypothesis of a relationship between somatropin therapy and leukemia.

Pediatric Patients With Turner Syndrome

TS children with short stature were treated with 0.37 mg/kg/week of Valtropin (somatropin injection) ® (5 mg = 15 IU formulation) (n=30) and 0.33 mg/kg/week of Eutropin™ INJ (1.33 mg = 4 IU formulation qualitatively identical to Valtropin (somatropin injection) ®) (n=60) during Study 1 and Study 2, respectively. Adverse events were reported by 10 (33.3%) children during Study 1. Most of these adverse events reflect very common pediatric illnesses. The most frequently (≥1.0%) reported adverse events were respiratory tract infections and ear infections (see Table 8). Turner syndrome patients are more prone to ear disorders and treatment with somatropin may increase the occurrence of these problems. One patient developed low titer antibodies to rhGH, and one other patient developed low titer anti-yeast antibodies which proved to be transient. During Study 2, a similar pattern of adverse events was observed (data not shown). Two patients developed low titer anti-rhGH antibodies at Month 12. Of interest, there were no reports in either study of benign intracranial hypertension, aggravation of preexisting scoliosis, slipped capital femoralepiphysis and hypertension. Somatropin-induced glucose intolerance will be discussed separately in the next paragraph. All patients with reported adverse events recovered during continued treatment.

During Study 1, a modest degree of glucose intolerance was observed in the 30 patients treated with Eutropin™ INJ for 12 months. No de novo cases of overt diabetes mellitus were diagnosed.

On the other hand, during Study 2, a much greater amount of glucose intolerance
was observed: a) 3 patients (with normal fasting blood glucose [FBG] values
at baseline [<100 mg/dL]) had FBG values between 130 and 145 mg/dL at Month
12 as well as at other study time points and (given the absence of follow-up
data after study termination) may have developed somatropin-induced de novo
diabetes mellitus; and b) 16 out of 41 patients (with normal FBG values at baseline)
had FBG values between 100-126 mg/dL at Month 12 (and 3 of these 16 patients
had FBG values >126 mg/dL transiently during the study). Since the amount
of somatropin administered in Study 2 (0.33 mg/kg/week) was slightly less than
the amount administered in Study 1 (0.37 mg/kg/week), these findings are difficult
to interpret. It is possible that some of these patients were not actually fasting
when blood samples were taken. See PRECAUTIONS (General) regarding the
well known potential of somatropin drug products to cause or unmask glucose
intolerance, especially in patients at greater inherent risk for diabetes mellitus,
i.e. patients with Turner syndrome.

Adult Patients With GHD

Adult GHD patients were treated with Eutropin™ INJ (1.33 mg = 4 IU formulation; qualitatively identical to Valtropin (somatropin injection) ®, a 5 mg = 15 IU formulation) vs. placebo during the pivotal clinical study. Ninety two patients received at least 3 months of treatment with Eutropin™ INJ (31 of these patients were treated with Eutropin™ INJ for an additional 3 months), and 61 patients received 3 months of treatment with placebo. Adverse events with an incidence of ≥5.0% are presented in Table 9.

The most frequent adverse event during treatment with Eutropin™ INJ was edema, which was reported more frequently than during placebo treatment. In some of these patients, edema resulted in down-titration of the dose of Eutropin™ INJ as per protocol. Myalgia was reported by 2 patients receiving Eutropin™ INJ and 2 patients treated with placebo. Arthralgia was reported by 2 patients receiving Eutropin™ INJ. There were no reports of carpal tunnel syndrome. These types of adverse events are thought to be related to the fluid accumulating effects of somatropin. Most adverse events reported during the study were mild in severity.

Adverse events
(Incidence ≥5.0% in either group)
n = number of patients

Eutropin™ INJ
(n = 92)

Placebo
(n = 61)

n

%

n

%

Edema

11

12.0

5

8.2

Upper respiratory tract infection

6

6.5

1

1.6

Urticaria

2

2.2

4

6.6

During the pivotal study in adult GHD patients, a modest degree of glucose
intolerance was observed in the 92 patients treated with Eutropin™ INJ for
at least 3 months (31 of whom were treated for an additional 3 months). Of note,
however, is the fact that 2 of the 26 patients in Group C with normal FBG values
at baseline (who were treated with Eutropin™ INJ for 3 months from Month 4
through the end of Month 6 after being crossed over from placebo) had FBG values
at Month 6 of 251 and 132 mg/dL. Absent follow-up data after study termination,
these patients may have developed somatropin-induced de novo diabetes mellitus.
In addition, 4 of these 26 patients had FBG values between 100-126 at Month
6. See PRECAUTIONS (General) regarding the well known potential of somatropin
drug products to cause or unmask glucose intolerance.

Eight of the 92 patients in this study were enrolled (as per protocol) with a preexisting diagnosis of diabetes mellitus (3 of these 8 patients in fact were being treated with oral agent combination therapy and the remaining 5 patients were without drug therapy). In general, these diabetic patients tolerated treatment with Eutropin™ INJ reasonably well, i.e. no post-treatment FBG values exceeded 164 mg/dL on-study.

Seventy five out of the 92 adult GHD patients in the pivotal study (~81%) had
preexisting central hypothyroidism and most of them were being treated with
thyroxine replacement therapy - usually in conjunction with panhypopituitarism.
None of these patients manifested clinical signs/symptoms of an exacerbation
of preexisting central hypothyroidism (serial thyroid function tests were not
obtained per protocol) during treatment with Eutropin™ INJ, i.e. there were
no changes in maintenance thyroxine dose nor adverse events related to the thyroid
during Eutropin™ INJ therapy. Furthermore, none of the remaining 17 patients
enrolled in this study manifested clinical evidence of de novo central hypothyroidism.
See PRECAUTIONS, DRUG INTERACTIONS.

Seventy five out of the 92 adult GHD patients in the pivotal study (~81%) also
had preexisting central hypoadrenalism and most of them were being treated with
glucocorticoid replacement therapy. None of these patients demonstrated convincing
clinical evidence of an exacerbation of preexisting central hypoadrenalism;
2 patients required an increase in hydrocortisone replacement dosages while
they were taking placebo approximately 2 months removed from treatment with
Eutropin™ INJ. Furthermore, none of the remaining 17 patients enrolled in this
study manifested clinical evidence of de novo central hypoadrenalism. See PRECAUTIONS,
DRUG INTERACTIONS.

DRUG INTERACTIONS

Somatropin inhibits 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) in adipose/hepatic tissue and may significantly impact the metabolism of cortisol and cortisone. As a consequence, in patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of the 11βHSD-1 enzyme.

Excessive glucocorticoid therapy may attenuate the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement therapy should be carefully adjusted in children with concomitant GH and glucocorticoid deficiency to avoid both hypoadrenalism and an inhibitory effect on growth.

Limited published data indicate that somatropin treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. However, formal drug interaction studies have not been conducted.